Carlo Negri

Both resistance training and aerobic training reduce hepatic fat content in type 2 diabetic subjects with nonalcoholic fatty liver disease (the RAED2 Randomized Trial).

Although lifestyle interventions are considered the first‐line therapy for nonalcoholic fatty liver disease (NAFLD), which is extremely common in people with type 2 diabetes, no intervention studies have compared the effects of aerobic (AER) or resistance (RES) training on hepatic fat content in type 2 diabetic subjects with NAFLD. In this randomized controlled trial, we compared the 4‐month effects of either AER or RES training on insulin sensitivity (by hyperinsulinemic euglycemic clamp), body composition (by dual‐energy X‐ray absorptiometry), as well as hepatic fat content and visceral (VAT), superficial (SSAT), and deep (DSAT) subcutaneous abdominal adipose tissue (all quantified by an in‐opposed‐phase magnetic resonance imaging technique) in 31 sedentary adults with type 2 diabetes and NAFLD. After training, hepatic fat content was markedly reduced (P < 0.001), to a similar extent, in both the AER and the RES training groups (mean relative reduction from baseline [95% confidence interval] −32.8% [−58.20 to −7.52] versus −25.9% [−50.92 to −0.94], respectively). Additionally, hepatic steatosis (defined as hepatic fat content >5.56%) disappeared in about one‐quarter of the patients in each intervention group (23.1% in the AER group and 23.5% in the RES group). Insulin sensitivity during euglycemic clamp was increased, whereas total body fat mass, VAT, SSAT, and hemoglobin A1c were reduced comparably in both intervention groups. Conclusion: This is the first randomized controlled study to demonstrate that resistance training and aerobic training are equally effective in reducing hepatic fat content among type 2 diabetic patients with NAFLD. (Hepatology 2013;58:1287–1295)

Serum Uric Acid Levels and Incident Chronic Kidney Disease in Patients With Type 2 Diabetes and Preserved Kidney Function

OBJECTIVE Recent studies have suggested an association between hyperuricemia and adverse renal outcomes in nondiabetic populations. Data on the relationship between hyperuricemia and the risk of incident chronic kidney disease (CKD) in type 2 diabetic patients with normal or near-normal kidney function are lacking. We determined whether baseline serum uric acid levels predict the subsequent development of CKD in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We followed 1,449 type 2 diabetic patients with normal kidney function and without overt proteinuria for 5 years for the occurrence of incident CKD (defined as overt proteinuria or estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2). RESULTS During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD (odds ratio [OR] 2.55 [95% CI 1.71–3.85], P < 0.001). After adjusting for age, sex, BMI, smoking status, diabetes duration, systolic blood pressure, antihypertensive treatment, insulin therapy, HbA1c, eGFR, and albuminuria, hyperuricemia was associated with an increased risk of incident CKD (adjusted OR 2.10 [1.16–3.76], P < 0.01). In continuous analyses, a 1-SD increment in the serum uric acid level was significantly associated with a 21% increased risk of CKD. CONCLUSIONS In type 2 diabetic individuals with preserved kidney function, hyperuricemia seems to be an independent risk factor for the development of incident CKD.

Metabolic Effects of Aerobic Training and Resistance Training in Type 2 Diabetic Subjects A randomized controlled trial (the RAED2 study)

OBJECTIVE To assess differences between the effects of aerobic and resistance training on HbA1c (primary outcome) and several metabolic risk factors in subjects with type 2 diabetes, and to identify predictors of exercise-induced metabolic improvement. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (n = 40) were randomly assigned to aerobic training or resistance training. Before and after 4 months of intervention, metabolic phenotypes (including HbA1c, glucose clamp–measured insulin sensitivity, and oral glucose tolerance test–assessed β-cell function), body composition by dual-energy X-ray absorptiometry, visceral (VAT) and subcutaneous (SAT) adipose tissue by magnetic resonance imaging, cardiorespiratory fitness, and muscular strength were measured. RESULTS After training, increase in peak oxygen consumption (VO2peak) was greater in the aerobic group (time-by-group interaction P = 0.045), whereas increase in strength was greater in the resistance group (time-by-group interaction P < 0.0001). HbA1c was similarly reduced in both groups (−0.40% [95% CI −0.61 to −0.18] vs. −0.35% [−0.59 to −0.10], respectively). Total and truncal fat, VAT, and SAT were also similarly reduced in both groups, whereas insulin sensitivity and lean limb mass were similarly increased. β-Cell function showed no significant changes. In multivariate analyses, improvement in HbA1c after training was independently predicted by baseline HbA1c and by changes in VO2peak and truncal fat. CONCLUSIONS Resistance training, similarly to aerobic training, improves metabolic features and insulin sensitivity and reduces abdominal fat in type 2 diabetic patients. Changes after training in VO2peak and truncal fat may be primary determinants of exercise-induced metabolic improvement.

Elevated Serum Uric Acid Concentrations Independently Predict Cardiovascular Mortality in Type 2 Diabetic Patients

OBJECTIVE There is limited information on whether increased serum uric acid levels are independently associated with cardiovascular mortality in type 2 diabetes. We assessed the predictive role of serum uric acid levels on all-cause and cardiovascular mortality in a large cohort of type 2 diabetic individuals. RESEARCH DESIGN AND METHODS The cohort included 2,726 type 2 diabetic outpatients, who were followed for a mean period of 4.7 years. The independent association of serum uric acid levels with all-cause and cardiovascular mortality was assessed by Cox proportional hazards models and adjusted for conventional risk factors and several potential confounders. RESULTS During follow-up, 329 (12.1%) patients died, 44.1% (n = 145) of whom from cardiovascular causes. In univariate analysis, higher serum uric acid levels were significantly associated with increased risk of all-cause (hazard ratio 19 [95% CI 1.12–1.27], P < 0.001) and cardiovascular (1.25 [1.16–1.34], P < 0.001) mortality. After adjustment for age, sex, BMI, smoking, hypertension, dyslipidemia, diabetes duration, A1C, medication use (allopurinol or hypoglycemic, antihypertensive, lipid-lowering, and antiplatelet drugs), estimated glomerular filtration rate, and albuminuria, the association of serum uric acid with cardiovascular mortality remained statistically significant (1.27 [1.01–1.61], P = 0.046), whereas the association of serum uric acid with all-cause mortality did not. CONCLUSIONS Higher serum uric acid levels are associated with increased risk of cardiovascular mortality in type 2 diabetic patients, independent of several potential confounders, including renal function measures.

Flutamide in the treatment of hirsutism: long-term clinical effects, endocrine changes, and androgen receptor behavior *

OBJECTIVE To investigate the long-term effects of treatment with low doses of flutamide on clinical and hormonal parameters, as well as on the androgen receptor status, in hirsute women. DESIGN Eighteen hirsute patients with regular menses were studied basally and during treatment with 125 mg flutamide, three times per day for 12 months. Barrier or intrauterine contraception was used during the study in sexually active women. Safety parameters were assessed throughout the study. Hirsutism, graded by the modified Ferriman-Gallwey score, and hormonal parameters were evaluated basally and at 4-month intervals during treatment. Gonadotropin-releasing hormone and ACTH stimulation tests were performed before and after 3 to 4 months of therapy. In addition, the concentration of androgen receptors in mononuclear leukocytes was measured, in both the follicular and luteal phases of the menstrual cycle, basally and after 4 months of flutamide treatment. RESULTS Flutamide was well tolerated in all women, with the noticeable exception of one patient who presented increased serum transaminase after 8 months of therapy. Hirsutism markedly improved in all women during the treatment (Ferriman-Gallwey score after 1 year: 4.1 +/- 0.5 versus 14.1 +/- 0.9). A reduction of serum androgens was found, whereas no change was observed in either basal or GnRH-stimulated gonadotropins or in the cortisol and 17 alpha-hydroxyprogesterone response to ACTH. Cycles remained ovulatory. Before treatment, the number of androgen receptors was higher in the luteal than in the follicular phase. This rhythmic differentiation disappeared after the patients had been given the antiandrogen drug. CONCLUSIONS Flutamide is effective in the treatment of hirsutism but requires constant surveillance of liver function. Androgen receptor blockade might be potentiated by a reduction of serum androgens. Flutamide affects androgen receptor behavior during the menstrual cycle. The meaning of this finding remains to be elucidated.

Outcome of long-term treatment with the 5α-reductase inhibitor finasteride in idiopathic hirsutism: clinical and hormonal effects during a 1-year course of therapy and 1-year follow-up *

OBJECTIVE To evaluate the long-term efficacy of the 5 alpha-reductase inhibitor finasteride in idiopathic hirsutism. DESIGN Prospective clinical study. SETTING Outpatients in a university hospital. PATIENT(S) Fourteen young women with idiopathic hirsutism. INTERVENTION(S) Finasteride, 5 mg once daily, was given for 12 months. MAIN OUTCOME MEASURE(S) Degree of hirsutism, graded by a modified Ferriman and Gallwey score, serum sex hormones, and serum and urinary markers of 5 alpha-reductase activity. Clinical outcome was evaluated up to and including the 1-year post-treatment period. RESULT(S) The Ferriman and Gallwey score showed a remarkable reduction after 12 months of finasteride treatment (4.4 +/- 0.7 versus 11.8 +/- 1.0; mean +/- SEM). Serum levels of the two 5 alpha-reductase activity markers, dihydrotestosterone and 3 alpha-androstanediol glucuronide, decreased, and urinary C19 and C21 5 beta:5 alpha steroid metabolite ratios consistently increased during finasteride administration. These changes were reversed readily after cessation of treatment. No significant adverse effect was reported. Nine of 14 women completed the 1-year post-treatment follow-up. Their hirsutism scores were increased substantially as compared with values recorded at the end of therapy, but still were lower than baseline values. CONCLUSION(S) The 5 alpha-reductase inhibitor finasteride is effective and well tolerated in longterm treatment of women with idiopathic hirsutism. Post-treatment follow-up suggests that drug effects on hair growth are sustained in the majority of subjects with this disorder.

Hyperinsulinemia Amplifies GnRH Agonist Stimulated Ovarian Steroid Secretion in Women with Polycystic Ovary Syndrome

CONTEXT In vitro data show that insulin may enhance basal and LH-stimulated ovarian androgen secretion, particularly in theca cells from women with polycystic ovary syndrome (PCOS). However, in vivo studies gave inconsistent results. OBJECTIVE The objective of the study was to assess whether hyperinsulinemia affects in vivo ovarian steroid secretion and steroid metabolism. DESIGN AND SETTINGS This was a controlled cross-sectional study, conducted in a tertiary care academic center. PARTICIPANTS Nine young PCOS women participated in the study. INTERVENTION Participants were submitted, in two separate days, to a GnRH agonist stimulation (buserelin 100 μg, s.c.), during a 17-h hyperinsulinemic (80 mU/m(2) · min) euglycemic clamp and, as a control, during saline infusion. Adrenal steroid secretion was suppressed by dexamethasone. MAIN MEASURES During both protocols, before and after GnRH agonist stimulation, serum insulin, gonadotropins, cortisol, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, estradiol, and urinary androgen metabolites were measured. RESULTS Insulin increased from 25.1 ± 13.3 to 341.5 ± 102.6 mU/liter during the clamp, whereas it did not significantly change during saline infusion. Baseline steroids and gonadotropins were similar in the two protocols. During hyperinsulinemia, GnRH agonist-stimulated serum progesterone and androstenedione were significantly higher than during saline infusion, and 17-hydroxyprogesterone was of borderline significance. Moreover, 24 h after GnRH agonist stimulation, testosterone was higher after hyperinsulinemia. Serum gonadotropins and estradiol response did not differ between the protocols. Urinary androgen metabolites excretion significantly increased after GnRH agonist stimulation, but the increase was similar during insulin and saline infusions. CONCLUSIONS These in vivo data show that sustained hyperinsulinemia potentiates gonadotropin-stimulated ovarian androgen steroidogenesis. Insulin-induced increase in ovarian hormone secretion is not accompanied by an increased steroid metabolism.

Aortic and Mitral Annular Calcifications Are Predictive of All-Cause and Cardiovascular Mortality in Patients With Type 2 Diabetes

OBJECTIVE To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals. RESEARCH DESIGN AND METHODS We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992–2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality. RESULTS At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1–4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9–17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality. CONCLUSIONS Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.

Acute Effect of Insulin on Autonomic Regulation of the Cardiovascular System: A Study by Heart Rate Spectral Analysis

Insulin is suggested to have direct effects on the cardiovascular system but these are not well described. We assessed the possible influence of insulin on autonomic control of heart function. A 2‐h hyperinsulinaemic euglycaemic clamp was performed in 10 healthy women (mean age 21.7 ± 1.3 years), at two different insulin infusion rates: 80 mU m−2 and 400 mU m−2 min−1, in 7 and 3 subjects, respectively. Saline alone was infused in 4 controls. Power spectral analysis (PSA) of heart rate was recorded before and after 90–120 min of insulin infusion, as were blood pressure and heart rate. Although there were no significant changes in heart rate or blood pressure, PSA showed marked reductions of high frequency (HF) bands after insulin (2.60 ± 0.12 vs 2.09 ± 0.16 log ms2, p < 0.005), as at both low and high infusion rates (2.46 ± 0.13 to 2.14 ± 0.23 log ms2, p < 0.05, and 2.92 ± 0.18 to 1.98 ± 0.06 log ms2, p < 0.01, respectively). There were no significant changes of low frequency (LF) bands. Densities at LF and HF did not change significantly in control studies. As HF and LF are considered to reflect parasympathetic and mainly sympathetic control respectively, our observation of an increased LF/HF ratio (0.13 ± 0.10 vs 0.63 ± 0.13, p < 0.005) may be considered an index of relative sympathetic predominance induced by insulin infusion. We conclude that insulin affects the cardiovascular system, reducing vagal influence on the heart and inducing a relative hypersympathetic tone.

Triglyceride-high-density lipoprotein cholesterol is associated with microvascular complications in type 2 diabetes mellitus.

The purpose of this study was to evaluate whether a high triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio is associated with an increased incidence of retinopathy and chronic kidney disease (CKD) in type 2 diabetes mellitus. Individuals with type 2 diabetes mellitus (n = 979) with an estimated glomerular filtration rate greater than 60 mL/min and without retinopathy and cardiovascular disease at baseline were followed up for the incidence of diabetic retinopathy (diagnosed by retinography) and CKD (diagnosed by estimated glomerular filtration rate ≤60 mL/min/1.73 m(2)). On follow-up (mean, 4.9 years), 217 (22.2% of total) subjects experienced CKD and/or diabetic-specific retinal lesions (microvascular complication). Of these, 111 subjects developed isolated retinopathy, 85 developed CKD alone, and 21 developed both complications. The TG/HDL-C ratio was positively associated with an increased risk of incident retinopathy and/or CKD (composite microvascular end point) independently of age, sex, body mass index, diabetes duration, hemoglobin A(1c), hypertension, smoking history, low-density lipoprotein cholesterol, albuminuria, and current use of hypoglycemic, antihypertensive, lipid-lowering, or antiplatelet drugs (multivariable-adjusted odds ratio, 2.15; 95% confidence intervals, 1.10-4.25; P = .04). These findings suggested that the TG/HDL-C ratio was associated with an increased incidence of microvascular complications in individuals with type 2 diabetes mellitus without prior cardiovascular disease, independently of several potential confounders.